The complement system is the major effector of the humoral aspect of the immune system. The classical pathway of complement activation involves the binding of soluble components, such as certain classes and subclasses of antibodies, to antigen targets within the body. Conformational changes in the Fc regions of these bound antibodies expose binding sites for C1, a soluble component of the complement system in its inactive state. Upon stable binding, C1 undergoes conformational changes resulting in active protease activity of one of the C1 subcomponents. The protease activity initiates a cascade of highly regulated interactions between complement components. A result of the cascade is the assembly of a membrane attack complex (MAC) on target cells.
An important step in the cascade of interactions of complement activation is the step of converting the component C3 into active C3b because there is tremendous amplification of the activation signal during this step. Particularly, an individual C3 convertase is able to convert hundreds of molecules of C3 into C3b. Each C3b component, in turn, forms part of a C5 convertase, producing C5b. Each activated C5b molecule initiates the formation of the MAC. The MAC is a macromolecular structure that penetrates through the cell membrane to create a transmembrane pore. The pore disrupts the integrity of the membrane and allows ions and small molecules to freely diffuse through, leading to complement-dependent-cytolysis (CDC).
Monoclonal antibodies (mAbs) have emerged as a potentially powerful class of novel therapeutics for a number of diseases. For example, in the field of oncology, there are several marketed therapeutic mAbs for treatment of cancer, and there are hundreds of mAbs currently in clinical development (see J. Castillo, et al., Experimental Hematology 36:755-768 (2008)). Many of these therapeutic mAbs operate by activating the complement cascade leading to the assembly of MACs on transformed tumor cells, causing CDC. This therapeutic approach can be advantageous because the antibodies can be specifically targeted towards antigens that are specific to transformed tumor cells, thus avoiding many side effects resulting from existing treatments.
However, the therapeutic potential of therapeutic mAbs can be limited due to the ability of diseased cells to block killing by CDC through the expression of membrane complement regulatory proteins (CRPs), such as CD35, CD46, CD55, and CD59 (D. Gancz and Z. Fishelson, Molecular Immunology 46:2794-2800 (2009); J. Golay, et al., Blood 98:3383-3389 (2001); K. A. Gelderman et al., Laboratory Investigation: A Journal of Technical Methods and Pathology 82:483-493 (2002); and N. Donin et al., Clinical and Experimental Immunology 131:254-263 (2003)). CD46 and CD55 block the complement cascade at the C3 activation stage and CD59 prevents assembly of the MAC of complement (Z. Fishelson et al., Molecular Immunology 40:109-123 (2003)).
Therefore, there is a need for compositions and methods to reduce the presence of CD35, CD46, CD55, and CD59 on the surface of target cells in order to reduce CRP-mediated inhibition of the MAC of complement.